Caught in the Gap: A Case of Unexpected Lactate Elevation

What is included in the differential diagnosis for an elevated lactate concentration? How is a discrepant lactate concentration investigated? What interferences are important to consider? Could the “Lactate Gap” be used as a screen for identifying ethylene glycol poisoning? A 49-year-old male presented to the emergency department via emergency medical services approximately 2 hours after ingesting several gulps of an unknown liquid found in his garage in a self-harm attempt. En route, he vomited once. On arrival, he was tachycardic with a heart rate of 114 beats per minute (bpm), normotensive (blood pressure 124/60 mmHg), and had a normal respiratory rate with an oxygen saturation (SpO₂) of 98% on room air. His Glasgow Coma Scale score was 15, and he appeared well, with a normal physical examination. Initial laboratory investigations revealed an elevated measured plasma osmolality of 359 mOsm/kg [reference interval (RI): 275–295 mOsm/kg (mmol/kg)]. Basic metabolic panel results showed a sodium within the normal range (141 mmol/L RI: 135–145 mmol/L), an elevated chloride (113 mmol/L; RI: 98–107 mmol/L), and low total CO₂ (17 mmol/L RI: 22–29 mmol/L). Venous blood gas analysis demonstrated a pH of 7.38 (7.32–7.43), partial pressure of carbon dioxide (PCO₂) 32 mmHg (RI: 35–45 mmHg), and a bicarbonate (HCO₃⁻) of 19 mmol/L (22–29 mmol/L). Notably, blood lactate measured on the blood gas analyzer was markedly elevated at 9.1 mmol/L (RI: 0.5–2.2 mmol/L). Serum ethanol, salicylate, and acetaminophen concentrations were all undetectable. Calculated laboratory parameters showed a markedly elevated osmol gap of 64 mOsm/kg (mmol/kg) (measured osmolality − calculated osmolarity, where calculated osmolarity =2 × [Na⁺] + [BUN mg/dL/2.8] + [glucose mg/dL/18]) or (2 × [Na⁺ mmol/L] + [urea mmol/L] + [glucose mmol/L] in SI units, where BUN is blood urea nitrogen), significantly above the normal threshold [10 mOsm/kg; (mmol/kg)]. The anion gap was within normal limits at 11 mEq/L (mmol/L) ([Na⁺] − ([Cl⁻] + [HCO₃⁻])). Other than neutrophil (9.1; RI: 2.0–7.5 ×109/L) and leukocyte (11.8; RI: 4.0–11.0 ×109/L) counts that were slightly elevated, the other complete blood count results were unremarkable. Details of the patient’s biochemical results are presented in Table 1. Given the ingestion history and the presence of a high osmol gap, the regional poison center was consulted within 5 hours and toxic alcohol tests ordered. Patient test results on admission and before discharge. Bolded results indicate high (H) levels or low (L) levels. SI unit = Conventional unit × conversion factor: anion gap (mmol/L) = mEq/L × 1, osmolality (mmol/kg) = mOsm/kg × 1, urea (mmol/L) = mg/dL × 0.357, creatinine (µmol/L) = mg/dL × 88.4, glucose (mmol/L) = mg/dL × 0.0555, acetaminophen (umol/L) = ug/mL × 0.151, salicylate (mmol/L) = mg/dL × 0.0724, ethanol (mmol/L) = mg/dL × 0.217, methanol (mmol/L) = mg/dL × 0.312, isopropanol (mmol/L) = mg/dL × 0.166, acetone (mmol/L) = × 0.1722, EG (mmol/L) = mg/dL × 0.161 eGFR, estimated glomerular filtration rate; AST, aspartate aminotransferase; RBC, red blood cell; MCV, mean corpuscular volume. Lactate is a key intermediate in anaerobic metabolism and an important biomarker in the evaluation of critically ill patients. In the context of a patient with a high anion-gap metabolic acidosis, an elevated lactate may indicate tissue hypoperfusion, mitochondrial dysfunction, or impaired hepatic clearance due to a concerning cause such as sepsis, drug toxicity, or liver failure (1). In vivo, glucose is metabolized through glycolysis to pyruvate. Under aerobic conditions, pyruvate is converted to acetyl-CoA, which enters the citric acid cycle, and is eventually converted to ATP through oxidative phosphorylation (1). Alternatively, under anaerobic conditions, or when mitochondrial function is impaired, pyruvate is converted to lactate by the enzyme lactate dehydrogenase (1). Lactate is primarily eliminated through the liver, when it is metabolized back to glucose through gluconeogenesis. Lactate accumulation results from increased production, due to tissue hypoxia, mitochondrial dysfunction, increased glycolysis, or decreased clearance (2). In the clinical setting, elevated lactate levels are often associated with high anion-gap metabolic acidosis and can reflect underlying critical illness. Notably, elevated lactate concentrations have been also observed in other causes of high anion-gap metabolic acidosis such as methanol and ethylene glycol (EG) poisoning. In methanol poisoning, the metabolite formate inhibits a key enzyme in oxidative phosphorylation, resulting in lactate accumulation, among other end-organ toxicities. In EG poisoning, the glycolate metabolite can interfere with certain lactate assays, resulting in a falsely elevated lactate (3, 4). Lactate can be measured via 2 main methods: blood gas analyzers and clinical chemistry platforms each employ different detection principles and have different specimen handling requirements. Blood gas analyzers typically use enzymatic amperometric methods; lactate oxidase (LOX) catalyzes the oxidation of lactate to pyruvate and hydrogen peroxide (H₂O₂), which is then detected electrochemically (Fig. 1). These systems are advantageous for their rapid turnaround time and minimal sample handling, using whole blood specimens. However, glycolate, a metabolite of EG, can cross-react with lactate oxidase due to structural similarities, potentially causing falsely elevated results (5). In contrast, chemistry analyzers typically use either colorimetric or enzymatic UV methods (Fig. 1). The colorimetric method involves LOX coupled with peroxidase and a chromogen system to yield a measurable color change. Alternatively, the UV method employs lactate dehydrogenase to catalyze the conversion of lactate to pyruvate with concomitant reduction of NAD⁺ to NADH, which is measured spectrophotometrically. These methods are generally more specific and less sensitive to EG metabolite cross-reaction but with longer turnaround times. Schematic diagrams of the 2 commonly used lactate measurement systems in the clinical laboratory. Lactate measurement is based on the formation of pyruvate, catalyzed by either lactate oxidase or lactate dehydrogenase. Adapted from “Lactate gap as a tool in identifying ethylene glycol poisoning,” Sagar AS, Jimenez CA, Mckelvy BJ, BMJ Case Reports 2018, bcr-2018-224243, ©2018, with permission from BMJ Publishing Group Ltd. A “lactate gap” is defined as a discordance between lactate concentrations measured using different analytical methodologies, most notably between blood gas analyzers and central laboratory plasma assays. This discrepancy can be clinically significant and may lead to diagnostic uncertainty, particularly in scenarios where elevated lactate levels are used to assess hypoperfusion or metabolic derangements. Clinically, a lactate gap may be observed in patients presenting with features of high anion-gap metabolic acidosis, including altered mental status, hyperventilation, hypotension, and signs of end-organ hypoperfusion (6). However, the lactate values reported may vary depending on the method used, potentially leading to delayed or inappropriate management. The phenomenon is most classically described in EG poisoning, where glycolate, a major toxic metabolite, can cross-react with lactate oxidase in blood gas analyzers, falsely elevating measured lactate concentrations (7). In contrast, laboratory-based lactate dehydrogenase assays are more specific for L-lactate and typically do not exhibit the same interference. A study by Tintu et al. evaluated the impact of EG and its metabolites on commonly used lactate assays and found that assay interference varied based on the microbial source of LOX. Colorimetric methods using LOX from Pediococcus sp. showed no interference from glycolate or glyoxylic acid, whereas assays employing LOX from Aerococcus viridans or amperometric methods using Pediococcus sp. demonstrated significant interference. These findings underscore the importance of assay selection when evaluating lactate in suspected EG intoxication (8). The biochemical profile associated with a lactate gap typically includes an elevated anion gap, increased osmol gap, acute kidney injury, and discordant lactate results between a chemistry analyzer and blood gas device (9, 10). In such cases, additional laboratory parameters such as toxic alcohol screening, along with a careful medication and exposure history, are important. The recognition of a lactate gap is critical (when available), particularly in emergency settings, as it may serve as a diagnostic clue to EG poisoning, prompting timely initiation of antidotal therapy, and consultations with toxicology and nephrology for hemodialysis. In laboratories offering lactate on both a blood gas analyzer and chemistry platform, assessing a discordant finding between the 2 methods may serve as a screen for EG poisoning in clinical settings where EG testing is sent out and might take a considerable amount of time before results are received. The regional poison center recommended obtaining serum ethanol, methanol, EG, acetone, and isopropanol concentrations, empirically initiating fomepizole therapy (an alcohol dehydrogenase inhibitor), and administering adjunctive cofactors—pyridoxine, thiamine, and leucovorin—to support nontoxic metabolic pathways for methanol and EG. Given the elevated lactate in the context of possible EG ingestion, measurement using a chemistry analyzer was recommended to confirm the result. Plasma lactate measured on the chemistry analyzer was significantly lower at 1.4 mmol/L, compared to the initial 9.1 mmol/L from the blood gas analyzer. Approximately 5 hours after presentation, the serum EG concentration returned markedly elevated at 237 mg/dL (38.2 mmol/L) (cutoff: <0.6 mg/dL; <0.1 mmol/L). The other toxic alcohols returned negative and were ruled out. The patient underwent hemodialysis to enhance the elimination of EG and its toxic metabolites. Repeat laboratory results postdialysis, demonstrated an EG concentration of 32 mg/dL and a pH of 7.46, PCO₂ 42 mmHg, and HCO₃⁻ 30 mmol/L. Plasma lactate measured 2.1 mmol/L on the blood gas analyzer and 1.5 mmol/L on the chemistry analyzer. The instructions for use of the blood gas analyzer (Werfen GEM 4000) reports positive interference from glycolate, with a bias of +0.4 mmol/L at a glycolic acid concentration of 0.250 mmol/L. At discharge, plasma lactate measured on the blood gas analyzer and on the chemistry analyzer were both within the reference interval (0.5–2.2 mmol/L). The observed discrepancy (0.6 mmol/L) was consistent with the known potential for glycolate-related positive bias, particularly in the context of resolving EG toxicity. Clinically, the patient remained asymptomatic. He was medically cleared on hospital day 2 and referred to psychiatry for further assessment. In this case, the discordance between an elevated lactate measured by the blood gas analyzer and the patient’s clinical presentation of EG ingestion with a high osmol gap raised suspicion for analytical interference. Repeat lactate measurement on a chemistry analyzer confirmed a near-normal lactate level, consistent with EG ingestion and glycolate cross-reactivity. This is consistent with other published cases where EG metabolites resulted in a lactate gap (6, 11). To manage such scenarios, laboratories should identify the susceptibility of their assays to interference. In settings where discrepant lactate results are noted between blood gas and chemistry analyzer assays, laboratories could implement a comment suggesting that this difference could be due to interference caused by EG metabolites, and that further testing (i.e., glycol testing) is recommended. If lactate is routinely performed on a blood gas method with known susceptibility to glycolate interference, patients with an elevated osmolar gap, elevated or borderline anion gap, low bicarbonate, and an elevated lactate could have a comment appended to the report suggesting contact with the laboratory to seek further investigation for potential interference if the clinical picture is not consistent with lactic acidosis. This could prompt the laboratory to repeat testing on an alternate chemistry platform (when available) and help to start a discussion about possible EG poisoning with the clinical team. This approach could improve diagnostic accuracy and support timely management in critical care settings. While the lactate gap is a valuable diagnostic clue in suspected EG poisoning, many clinicians may be unfamiliar with this phenomenon or the analytical nuances underlying lactate measurement. When recognized, this discordance can be used advantageously by poison centers and healthcare providers to support a working diagnosis of toxic alcohol ingestion. This underscores the importance of strong collaboration between clinicians, poison centers, and clinical biochemists to ensure appropriate interpretation of discordant results and timely patient management. Additionally, IVD manufacturers should clearly disclose known assay interferences in their package inserts, including those from EG metabolites, which can cause falsely elevated lactate on certain devices and platforms. Clinicians and laboratories alike must be aware of these method-specific limitations. Lactate measurement varies by platform; blood gas analyzers use lactate oxidase amperometry, while chemistry analyzers use enzymatic colorimetric or UV methods. Analytical interferences, particularly from EG metabolites, can falsely elevate lactate measured by blood gas analyzers. Cross-verifying lactate on a chemistry analyzer can help distinguish true hyperlactatemia from assay interference. Elevated osmolar gaps should raise suspicion for toxic alcohol ingestion, even if anion gaps are normal. Early recognition of false lactate elevations is crucial to guide appropriate antidotal therapy and prevent mismanagement. Nonstandard Abbreviations: SpO₂, oxygen saturation; PCO2, partial pressure of carbon dioxide; HCO3−, bicarbonate; BUN, blood urea nitrogen; EG, ethylene glycol; LOX, lactate oxidase. Author Contributions: The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Meshach Asare-Werehene (Conceptualization-Equal, Formal analysis-Equal, Investigation-Equal, Writing—original draft-Lead), Emily Austin (Conceptualization-Equal, Investigation-Equal, Project administration-Equal, Writing—review & editing-Equal), Daniel Beriault (Resources-Equal, Supervision-Equal, Writing—review & editing-Equal), and Sarah Delaney (Conceptualization-Equal, Investigation-Equal, Project administration-Lead, Supervision-Lead, Writing—review & editing-Equal) Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

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